NMDA receptor activation inhibits α-secretase and promotes neuronal amyloid-β production

被引:178
作者
Lesné, S
Ali, C
Gabriel, C
Croci, N
MacKenzie, ET
Glabe, CG
Plotkine, M
Marchand-Verrecchia, C
Vivien, D
Buisson, A
机构
[1] Univ Caen, UMR 6185, Ctr Cyceron, CNRS, F-14074 Caen, France
[2] Univ Caen, Equipe Inst Natl Sante & Rech Med Avenir tPA Work, F-14074 Caen, France
[3] Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA
[4] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA
[5] Univ Paris 05, Fac Sci Pharmaceut & Biol, Pharmacol Lab, EA2510, F-75006 Paris, France
关键词
amyloid; APP; secretase; glutamate receptors; calmodulin; neurons;
D O I
10.1523/JNEUROSCI.0849-05.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-beta (A beta) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of A beta. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-beta precursor protein (KPI-APP) followed by a shift from beta-secretase to beta-secretase-mediated APP processing. This shift is a result of the inhibition of the beta-secretase candidate tumor necrosis factor-alpha converting enzyme ( TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal A beta secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase A beta production and represent a causal risk factor for developing AD.
引用
收藏
页码:9367 / 9377
页数:11
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